Montgomery J. A., et al., Journal of Medicinal Chemistry, 36:55-69 (1993) disclose a series of 9-(arylmethyl) derivatives of 9-deazaguanine useful as inhibitors of purine nucleoside phosphorylase. Additionally, Secrist III J. A., et al., Journal of Medicinal Chemistry, 36:1847-1854 (1993) disclose a series of 9-alicyclic and 9-heteroalicyclic derivatives of 9-deazaguanine useful as inhibitors of purine nucleoside phosphorylase. Inhibitors of purine nucleoside phosphorylase may have therapeutic value in the treatment of T-cell proliferative diseases such as T-cell leukemias or lymphomas, in the suppression of host-vs-graft response in organ transplants and in the treatment of T-cell mediated autoimmune diseases such as rheumatoid arthritis and lupus.
U.S. Pat. Nos. 4,923,872, 4,988,702, and 5,061,707 which are herein incorporated by reference, disclose a novel series of pyrrolo[3,2-d]pyrimidines.
The compounds disclosed in U.S. Pat. Nos. 4,923,872, 4,988,702, and 5,061,707 are useful for treating autoimmune disease, gout, psoriasis, and rejection of transplantation. Particularly valuable in the aforementioned therapeutic categories is 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one. The aforementioned compound has been prepared by catalytic hydrogenation of 2-amino-1,6-dihydro-5-nitro-6-oxo-.alpha.-(3-thienylmethyl)-4-pyrimidin eacetonitrile.
Church R. F. R., et al., Journal of Organic Chemistry, 36:723 (1971) disclosed the replacement of a diazonium salt with hydrogen using a palladium catalyst in the presence of formaldehyde. Thus, Church R. F. R., et al., hydrogenated the diazonium salt of 9-amino-7-nitro-6-demethyl-6-deoxytetracycline to afford 7-nitro-6-demethyl-6-deoxytetracycline. In a footnote the previous authors note that the replacement of the diazonium group by hydrogen by this procedure is unusual. This is the only literature disclosure of catalytic reduction of diazonium salts with a precious metal or Raney-type nickel catalyst to replace an amino group with hydrogen of which we are aware.
The object of the present invention is an improved process for preparing 2-amino-3,5-dihydro-7-substituted-4H-pyrrolo[3,2-d]pyrimidine-4-ones and in particular 2-amino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one from 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-o ne. The present method involves the replacement of an amino group with hydrogen through the diazonium salt by catalytic reduction over a precious metal or Raney-type nickel catalyst in an atmosphere of hydrogen. The present process uses hydrogen gas rather than formaldehyde. This has several advantages. The workup of hydrogenations is simpler than reactions using formaldehyde since hydrogen gas is released and the catalyst is removed by filtration; and formaldehyde is toxic, a possible carcinogen, a sensitizer, and an irritant which requires the use of special equipment and extensive personal protective gear.
Thus, we have surprisingly and unexpectedly found an improved process to prepare 2-amino-3,5-dihydro-7-substituted-4H-pyrrolo[3,2-d]pyrimidin-4-ones which uses less hazardous reagents and does not require chromatography to purify the product. Therefore, the present process is amenable to large-scale synthesis. It is also surprising that the 6-amino group and not the 2-amino group is selectively diazotized and replaced.